Inflammasome Activation Triggers Systemic Coagulation in Sepsis

脓毒症中炎症小体激活引发全身凝血

• 批准号: 10645452
• 负责人: ZHENYU Li
• 金额: $ 42.95万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10645452
• 关键词: Apoptosis; Bacteria; Bacterial Infections; Blood Coagulation Disorders; Blood Coagulation Factor; Bone Marrow; Burkholderia; CASP1 gene; Cells; Cessation of life; Clinical; Coagulation Process; Complication; Consumption; Data; Development; Disease; Disseminated Intravascular Coagulation; Escherichia coli; Family; Fibrinogen; Flagellin; Functional disorder; Goals; Gram-Negative Bacteria; In Vitro; Infection; Inflammasome; Infusion procedures; Injections; Intervention; Knockout Mice; Lead; Link; Modeling; Molecular; Morbidity - disease rate; Mus; Myelogenous; Needles; Organ; Outcome; Pathway interactions; Patients; Peripheral; Phagocytosis; Physiological; Plasma; Play; Proteins; Prothrombin time assay; Pseudomonas aeruginosa; Reagent; Research Project Grants; Rod; Role; Salmonella; Sepsis; Septic Shock; Testing; Thrombocytopenia; Thromboplastin; Thrombosis; Thrombus; Tissues; Type III Secretion System Pathway; Work; antithrombin III-protease complex; base; cecal ligation puncture; driving force; in vivo; insight; intravenous injection; macrophage; monocyte; mortality; mouse model; multidisciplinary; new therapeutic target; protein E; release factor; septic patients; targeted treatment

Abstract Septic shock is invariably associated with systemic coagulation leading to thrombus formation. Sepsis-related organ dysfunction has been attributed to microvascular thrombosis. Mortality rate doubles in septic patients with disseminated intravascular coagulation (DIC). DIC is even considered as a sign that “death is coming”. Previous studies have demonstrated the important roles of tissue factor (TF) in sepsis-associated DIC. However, the mechanism leading to TF release, which triggers systemic coagulation in sepsis, is unknown. Recent in vitro studies revealed that bacterial components (flagellin, the rod protein of the type III secretion system (T3SS), or LPS) induce programmed cell death (called pyroptosis) of macrophages through activation of inflammasome pathways. We show that intravenous injection of a T3SS rod protein E. coli, EprJ, induced depletion of peripheral monocytes and macrophages in tissues. Importantly, injection of EprJ or LPS, which elicit canonical and noncanonical inflammasome activation, respectively, induced systemic coagulation activation, as evident by prolonged prothrombin time (PT) due to increased consumption of coagulation factors, thrombocytopenia, increased plasma levels of thrombin-antithrombin complex (TAT), and reduced plasma fibrinogen levels. Thus, our findings made connections between the in vitro and in vivo observations and suggested monocyte/macrophage pyroptosis as a trigger of DIC in sepsis. The goal of this application is to delineate the underlying mechanisms by which inflammasome activation and pyroptosis trigger DIC in sepsis. Specific Aim 1 will establish inflammasome activation and pyroptosis as a common mechanism for DIC induced by bacterial infection. The working hypothesis is that bacteria and bacterial components from different strains elicit DIC through Inflammasome activation and pyroptosis. We will use a combination of various deficient mice to elucidate the role of inflammasome activation and pyroptosis in DIC elicited by Gram-negative bacteria. Specific Aim 2 is to identify the molecular mechanism of TF release from macrophages following inflammasome activation. We will also use the myeloid-specific TF knockout mice and a low TF mouse model to elucidate whether DIC elicited by the bacterial components depends on release of TF from macrophages. Specific Aim 3 will demonstrate the role of inflammasome activation in sepsis-associated coagulopathy. We will use the cecal ligation and puncture (CLP) sepsis model and bacterial infusion sepsis model to investigate the role of inflammasome activation and pyroptosis in coagulation. Completion of the proposed studies will demonstrate the molecular mechanism of systemic coagulation is sepsis. Such findings would have profound ramifications for the identification of new drug targets for DIC, the deadly complication of sepsis.

摘要

项目成果

Inhibiting NINJ1-dependent plasma membrane rupture protects against inflammasome-induced blood coagulation and inflammation.

抑制 NINJ1 依赖性质膜破裂可防止炎症体诱导的凝血和炎症。

• DOI: 10.1101/2023.08.30.555561
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Cui,Jian;Li,Hua;Zhang,Guoying;Zhang,Yan;Yang,Ling;Sim,MarthaMS;Wood,JeremyP;Wei,Yinan;Li,Zhenyu;Wu,Congqing
• 通讯作者: Wu,Congqing

Inflammasome activation and pyroptosis mediate coagulopathy and inflammation in Salmonella systemic infection.

• DOI: 10.1016/j.micres.2023.127460
• 发表时间: 2023-10
• 期刊: MICROBIOLOGICAL RESEARCH
• 影响因子: 6.7
• 作者: Pandeya, Ankit;Zhang, Yan;Cui, Jian;Yang, Ling;Li, Jeffery;Zhang, Guoying;Wu, Congqing;Li, Zhenyu;Wei, Yinan
• 通讯作者: Wei, Yinan

Calcium Ion Chelation Preserves Platelet Function During Cold Storage.

• DOI: 10.1161/atvbaha.120.314879
• 发表时间: 2021-01
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Xiang B;Zhang G;Zhang Y;Wu C;Joshi S;Morris AJ;Ware J;Smyth SS;Whiteheart SW;Li Z
• 通讯作者: Li Z